ALTERATIONS IN TELOMERASE REVERSE TRANSCRIPTASE AND CANCER GENES IN BLADDER CANCER

Abstract

Bladder cancer (BC) is the most common malignancy of the urinary tract worldwide and the most expensive to treat. Many genes have been implicated in disease initiation and progression. Analysis of genetic alterations in BC may provide information about the causal basis of bladder tumorigenesis and may identify new therapeutic options for BC. We sequenced 54 urothelial tumors from patients with BC using exome NGS and targeted sequencing. We observed rare, deleterious germline variants in 50% of cases including variants in known cancer genes (KDM6A, BRCA2, RB1, FGFBP1, TP53, and TSC1). We found 3 genes not previously reported with frequent somatic mutations in BC, BAP1, CHD1 and GCNIL1. BAP1 was altered in 15% of primary tumors (n=54) and mutations were associated with somatic KDM6A alterations. In addition, we characterized 96 variants in the TERT promoter in BC tumors. Analyses of telomere length showed significantly shorter telomeres in tumor tissue versus adjacent normal tissue (p=0.004) indicating TERT protein activity was potentially overwhelmed by the higher proliferation rates of tumor cells or that TERT may act to promote cancer through telomere length-independent mechanisms.